Topical ophthalmic or otic solution formulations containing moxifloxacin hydrochloride and dexamethasone phosphate

ABSTRACT

Topical ophthalmic and otic solution compositions of moxifloxacin and dexamethasone phosphate are disclosed.

This application is a continuation application of U.S. Ser. No.12/276,823, filed Nov. 24, 2008, now U.S. Pat. No. 7,888,370 whichclaims priority to U.S. Provisional Application, U.S. Ser. No.60/990,452, filed Nov. 27, 2007.

BACKGROUND OF THE INVENTION

This invention relates to solution formulations of moxifloxacin anddexamethasone phosphate suitable for topical administration to the eyeor ear.

Moxifloxacin is a known antibiotic compound. See, for example, U.S. Pat.Nos. 4,990,517 and 5,607,942. A topically administrable ophthalmicsolution containing moxifloxacin is commercially available as VIGAMOX®(moxifloxacin HCl ophthalmic solution), 0.5% as base, from AlconLaboratories, Inc. See U.S. Pat. No. 6,716,830. The '830 patentdiscloses compositions specifically formulated for topical applicationto ophthalmic, otic, and nasal tissues. The '830 patent disclosesmoxifloxacin compositions optionally containing an anti-inflammatoryagent. Disclosed anti-inflammatory agents include steroidal andnon-steroidal anti-inflammatory agents. According to the '830 patent,the preferred steroidal anti-inflammatory agents for ophthalmic and oticuse include dexamethasone, loteprednol, rimexolone, prednisolone,fluorometholone, and hydrocortisone. A suspension composition containingmoxifloxacin and dexamethasone (micronized) and having a pH of 5.5 isprovided in Example 2 of the '830 patent. The '830 patent does notspecifically disclose any solution compositions containing moxifloxacinand dexamethasone phosphate.

Dexamethasone phosphate is a known form of dexamethasone. See, forexample, U.S. Pat. No. 2,939,873. This form of dexamethasone has beenused in topical ophthalmic and otic compositions. See, for example, U.S.Pat. No. 5,679,665.

What is needed are stable, preserved, multi-dose solution compositionsof moxifloxacin and dexamethasone that are suitable for topicaladministration to the eye and ear.

SUMMARY OF THE INVENTION

The compositions of the present invention are aqueous compositions ofmoxifloxacin and dexamethasone. The compositions are stable, preserved,multi-dose solution compositions. The compositions, which are topicallyadministrable to the eye or ear, consist essentially of moxifloxacinhydrochloride, dexamethasone phosphate, edetate disodium, an ionictonicity adjusting agent, boric acid, a nonionic surfactant, and eitherbenzalkonium chloride or sorbitol. The compositions have a pH of7.5-8.1.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, all ingredient concentrations are presentedin units of % weight/volume (% w/v).

Moxifloxacin is preferably present in the compositions of the presentinvention in the form of a pharmaceutically acceptable salt. Mostpreferably, moxifloxacin is present in the form of moxifloxacinhydrochloride. The compositions contain moxifloxacin in an amountequivalent to about 0.5% as the free base. The amount of moxifloxacinhydrochloride in the compositions of the present invention is 0.5-0.6%,and is most preferably 0.545%, which is equivalent to 0.5% moxifloxacinas base.

In addition to moxifloxacin, the aqueous compositions of the presentinvention contain dexamethasone phosphate. Dexamethasone phosphate isthe required form of dexamethasone. Other known forms of dexamethasone,such as the 21-alcohol or 21-acetate form, do not permit the compositionto be a solution composition. Suspension compositions are not asdesirable for topical administration to the eye or ear as solutioncompositions because suspensions do not penetrate ophthalmic or otictissues as well as solutions. The compositions of the present inventioncontain dexamethasone phosphate in an amount of about 0.1-0.12%.Preferably, the compositions of the present invention contain apharmaceutically acceptable salt of dexamethasone phosphate in an amountequivalent to about 0.1-0.12% dexamethasone phosphate. For example, thecompositions of the present invention may contain dexamethasone sodiumphosphate in an amount of 0.10-0.132%. Most preferably, the compositionsof the present invention contain 0.11% dexamethasone sodium phosphate,which is equivalent to 0.1% dexamethasone phosphate. Preferably, thecompositions of the present invention contain dexamethasone in the formof dexamethasone sodium phosphate.

The compositions of the present invention contain boric acid in anamount from 0.2-0.4%, preferably 0.3%.

Edetate disodium is present in the compositions of the present inventionin an amount of 0.005-0.02%. Most preferably, the edetate disodium ispresent in an amount of 0.01%.

An ionic tonicity adjusting agent is added to the compositions of thepresent invention in an amount sufficient to cause the final compositionto have an osmolality of 270-330 mOsm/Kg. Preferably, the ionic tonicityadjusting agent is sodium chloride and is present in an amount of0.5-0.75%. Most preferably, the compositions of the present inventioncontain 0.62% NaCl.

The compositions of the present invention contain an otically andophthalmically acceptable non-ionic surfactant, such as a polysorbatesurfactant, a block copolymer of ethylene oxide and propylene oxidesurfactant (e.g., a pluronic or tetronic surfactant), or tyloxapol.Preferably, the compositions contain the non-ionic surfactant in anamount of 0.04-0.06%. Most preferably, the non-ionic surfactant istyloxapol and the amount of tyloxapol in the compositions of the presentinvention is 0.05%.

The compositions contain a preservative ingredient or apreservation-enhancing ingredient selected from the group consisting ofbenzalkonium chloride and sorbitol. Preferably, the compositions of thepresent invention contain benzalkonium chloride if they are intended fortopical otic administration and sorbitol if they are intended fortopical ophthalmic administration. If present, the amount ofbenzalkonium chloride in the compositions is 0.005-0.015%, preferably0.01%. If present, the amount of sorbitol in the compositions of thepresent invention is 0.1-0.3%, preferably 0.2%.

The pH of the aqueous solutions of the present invention is adjustedwith an ophthalmically acceptable pH-adjusting agent. Ophthalmicallyacceptable pH adjusting agents are known and include, but are notlimited to, hydrochloric acid (HCl) and sodium hydroxide (NaOH). Thecompositions of the present invention preferably contain NaOH or HCl toobtain the desired pH. The compositions of the present invention areformulated and maintained within a narrow pH range in order to keep thecompositions stable over a commercially acceptable shelf-life period.The compositions of the present invention have a pH of 7.5-8.1, and mostpreferably 7.8-8.0.

The compositions of the present invention are preferably packaged inmulti-dose plastic containers designed to deliver drops to the eye orear. Preferably the plastic is low density polyethylene (LDPE) orpolypropylene. Most preferably, the plastic is LDPE.

The following examples are intended to illustrate, but not limit, thepresent invention.

Example 1

Topical Ophthalmic Solution Ingredient Formulation A (% w/v)Moxifloxacin 0.5-0.6 Hydrochloride Dexamethasone Sodium 0.10-0.12Phosphate Edetate Disodium 0.005-0.02  NaCl  0.5-0.75 Boric Acid 0.2-0.4Sorbitol 0.1-0.3 Tyloxapol 0.04-0.06 NaOH/HCl q.s. pH 7.5-8.1 PurifiedWater q.s. 100

Example 2

Preferred Topical Ophthalmic Solution Ingredient Formulation B (% w/v)Moxifloxacin 0.545^(a) Hydrochloride Dexamethasone Sodium 0.11^(b)Phosphate Edetate Disodium 0.01^(c) NaCl 0.62 Boric Acid 0.3 Sorbitol0.2 Tyloxapol 0.05 NaOH^(d)/HCl q.s. pH 7.8-8.0 Purified Water q.s. 100^(a)0.545% is equivalent to 0.5% moxifloxacin as base ^(b)0.11% isequivalent to 0.1% dexamethasone phosphate ^(c)Edetate disodium,dehydrate is used ^(d)Sodium hydroxide equivalent to 0.0972% is added tofacilitate dissolution of moxifloxacin hydrochloride. Additional NaOHmay be added if required for pH adjustment.

Example 3

Topical Otic Solution Ingredient Formulation C (% w/v) Moxifloxacin0.5-0.6 Hydrochloride Dexamethasone Sodium 0.10-0.12 Phosphate EdetateDisodium 0.005-0.02  NaCl  0.5-0.75 Boric Acid 0.2-0.4 BenzalkoniumChloride 0.005-0.015 Tyloxapol 0.04-0.06 NaOH/HCl q.s. pH 7.5-8.1Purified Water q.s. 100

Example 4

Preferred Topical Otic Solution Ingredient Formulation D (% w/v)Moxifloxacin 0.545^(a) Hydrochloride Dexamethasone Sodium 0.11^(b)Phosphate Edetate Disodium 0.01^(c) NaCl 0.62 Boric Acid 0.3Benzalkonium Chloride 0.01 Tyloxapol 0.05 NaOH^(d)/HCl q.s. pH 7.8-8.0Purified Water q.s. 100 ^(a)0.545% is equivalent to 0.5% moxifloxacin asbase ^(b)0.11% is equivalent to 0.1% dexamethasone phosphate ^(c)Edetatedisodium, dehydrate is used ^(d)Sodium hydroxide equivalent to 0.0972%is added to facilitate dissolution of moxifloxacin hydrochloride.Additional NaOH may be added if required for pH adjustment.

Example 5

Physical stability studies (clarity, precipitates by visual inspection,and pH stability) were conducted for three lots of the composition ofExample 4. Samples of the composition were stored in 8 mL opaque LDPEbottles under the following conditions: 4° C./35% relative humidity; 25°C./40% relative humidity; 25° C./40% relative humidity (bottles storedin horizontal position); 30° C./65% relative humidity; 40° C./<25%relative humidity; light cabinet (25° C./40% relative humidity, with anoverall illumination of not less than 1.2 million lux hours andintegrated near ultraviolet energy of not less than 200watt-hours/square meter); light cabinet and LDPE bottle in cardboardbox; cycling conditions (CY) 1 week with a freeze at −20° C. for 28hours, then thaw at 30° C. for 28 hours, for a total of 3 cycles in aweek. The results are shown in Tables 1-3.

TABLE 1 Clarity Age Storage Condition (Weeks) Lot 1 Lot 2 Lot 3 Initial0 Clear, NMT Ph. Eur. I* Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 4°C./35% RH 52 Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph.Eur. I 25° C./40% RH 26 Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. IClear, NMT Ph. Eur. I 52 Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. IClear, NMT Ph. Eur. I 25° C./40% RH, 13 Clear, NMT Ph. Eur. I Clear, NMTPh. Eur. I Clear, NMT Ph. Eur. I Horizontal 26 Clear, NMT Ph. Eur. IClear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 39 Clear, NMT Ph. Eur. IClear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 52 Clear, NMT Ph. Eur. IClear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 78 Clear, NMT Ph. Eur. IClear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 30° C./65% RH 52 Clear, NMTPh. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 40° C./<25% RH 13Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I 26Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I LC 6Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I LC/PKG6 Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I CY:−20, 30 1 Clear, NMT Ph. Eur. I Clear, NMT Ph. Eur. I Clear, NMT Ph.Eur. I *“NMT Ph. Eur. I” means that the solution is clearer thanEuropean Pharmacopeal clarity standard number I.

TABLE 2 Precipitates Storage Age Condition (Weeks) Lot 1 Lot 2 Lot 3Initial 0 None None None 4° C./35% RH 52 None None None 25° C./40% RH 26None None None 52 None None None 25° C./40% RH, 13 None None NoneHorizontal 26 None None None 39 None None None 52 None None None 78 NoneNone None 30° C./65% RH 52 None None None 40° C./<25% RH 13 None NoneNone 26 None None None LC 6 None None None LC/PKG 6 None None None CY:−20, 30 1 None None None

TABLE 3 pH Stability Storage Age Condition (Weeks) Lot 1 Lot 2 Lot 3Initial 0 7.92 7.97 7.98 4° C./35% RH 52 7.89 7.89 7.90 25° C./40% RH 267.83 7.88 7.85 52 7.89 7.89 7.90 25° C./40% RH, 13 7.89 7.90 7.93Horizontal 26 7.83 7.89 7.86 39 7.86 7.90 7.89 52 7.89 7.89 7.90 78 7.877.90 7.92 30° C./65% RH 52 7.88 7.88 7.88 40° C./<25% RH 13 7.89 7.917.94 26 7.83 7.88 7.85 LC 6 7.85, 7.86 7.90 7.90 LC/PKG 6 7.90 7.96 7.97CY: −20, 30 1 7.92 7.91 7.91

Example 6

The stabilizing effect of various concentrations of tyloxapol in thecomposition of Example 4 was investigated in a freeze-thaw cyclingstudy. Each cycle consisted of 24 hours at −20° C. followed by 24 hoursat room temperature. The compositions were stored in LDPE containerssterilized using ethylene oxide gas or in glass containers. The resultsare shown in Tables 4 (LDPE containers) and 5 (glass containers).

TABLE 4 (LDPE Containers) Tyloxapol Concentration 0.05% CycleObservations 0% 0.02% 0.03% 0.04% (Example 4) Initial Clarity ClearClear Clear Clear Clear Color Yellow Yellow Yellow Yellow YellowParticles by No particles No particles No particles No particles Noparticles Visual Observation pH 7.909 7.926 7.917 7.915 7.910 Cycle 1Clarity Clear Clear Clear Clear Clear Color Yellow Yellow Yellow YellowYellow Particles by No particles No particles No particles No particlesNo particles Visual Observation Cycle 2 Clarity Clear Clear Clear ClearClear Color Yellow Yellow Yellow Yellow Yellow Particles by No particlesNo particles No particles No particles No particles Visual ObservationpH 7.886 7.900 7.882 7.897 7.893 Cycle 3 Clarity Clear Clear Clear ClearClear Color Yellow Yellow Yellow Yellow Yellow Particles by No particlesNo particles No particles No particles No particles Visual ObservationCycle 4 Clarity Clear Clear Clear Clear Clear Color Yellow Yellow YellowYellow Yellow Particles by 4-5 2-3 particles No particles No particlesNo particles Visual particles in in Observation 4 bottles 4 bottles pH7.877 7.893 7.918 7.903 7.906

TABLE 5 (Glass Containers) Tyloxapol Concentration 0.05% CycleObservations 0% 0.02% 0.03% 0.04% (Example 4) Initial Clarity ClearClear Clear Clear Clear Color Yellow Yellow Yellow Yellow YellowParticles by No particles No particles No particles No particles Noparticles Visual Observation pH 7.909 7.926 7.917 7.915 7.910 Cycle 1Clarity Clear Clear Clear Clear Clear Color Yellow Yellow Yellow YellowYellow Particles by No particles No particles No particles No particlesNo particles Visual Observation Cycle 2 Clarity Clear Clear Clear ClearClear Color Yellow Yellow Yellow Yellow Yellow Particles by No particlesNo particles No particles No particles No particles Visual ObservationpH 7.885 7.911 7.909 7.908 7.910 Cycle 3 Clarity Clear Clear Clear ClearClear Color Yellow Yellow Yellow Yellow Yellow Particles by No particlesNo particles No particles No particles No particles Visual ObservationCycle 4 Clarity Clear Clear Clear Clear Clear Color Yellow Yellow YellowYellow Yellow Particles by 15-20 10-15 9-11 particles 5-10 1-2 particlesVisual particles in particles in all bottles particles in allObservation all bottles in all in all bottles bottles bottles pH 7.8777.900 7.920 7.911 7.906

Example 7

The physical stability of the indicated moxifloxacin and dexamethasonephosphate solution compositions was tested and the results are shown inTables 6-9 below.

TABLE 6 Formulations at acidic pH (4.0 to 6.0) Component A B C D E FMoxifloxacin Hydrochloride 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a)0.545^(a) 0.545^(a) Dexamethasone Sodium 0.132^(b) 0.132^(b) 0.132^(b)0.132^(b) 0.132^(b) 0.132^(b) Phosphate Edetate Disodium 0.01 0.01 0.010.01 0.01 0.01 Boric Acid 0.3 0.3 0.3 0.3 0.3 0.3 Citric Acid,Monohydrate — — — 0.5 0.5 0.5 Sodium Chloride 0.62 0.5 0.5 — — —Glycerin — — — 1.6 1.6 1.6 Sorbitol 0.2 0.2 0.2 0.2 0.2 0.2 Tyloxapol0.05 0.05 0.05 0.05 0.05 0.05 NaOH/HCl qs qs qs qs qs qs 4.0 ± 0.1 5.0 ±0.1 6.0 ± 0.1 4.0 ± 0.1 5.0 ± 0.1 6.0 ± 0.1 Purified Water qs 100 qs 100qs 100 qs 100 qs 100 qs 100 Observations Precipitate^(c) Precipitate^(c)Precipitate^(c) Precipitate Precipitate Precipitate ^(a)0.545%Moxifloxacin hydrochloride is equivalent to 0.5% moxifloxacin as base.^(b)0.132% Dexamethasone sodium phosphate is equivalent to 0.1%dexamethasone. ^(c)The Moxifloxacin did not go into solution until thebatch was heated. However as the solution was allowed to cool, crystalsbegan to form in the solution and on the sides of the beaker. Note: ForFormulations D, E, and F the compounding procedure consisted of twoseparate parts: part I - Moxifloxacin solution and part II -Dexamethasone Phosphate solution. Both solutions appeared clear. Uponaddition of part II to part I, the solutions initially appeared clearbut after a few minutes of mixing the solutions became cloudy.Formulation E was brought down to pH 3.5 to see if the solution wouldbecome clear, but it did not.

TABLE 7 Component G H I J K L Moxifloxacin Hydrochloride 0.545^(a)0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) Dexamethasone SodiumPhosphate 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b)Edetate Disodium 0.01 0.01 0.01 0.01 0.01 0.01 Boric Acid 0.3 0.3 0.30.3 0.3 0.3 Sodium Chloride 0.44 0.44 0.36 0.36 0.26 0.19 Mannitol 0.50.5 — — — — Glycerin — — 0.5 0.5 0.8 1.0 Sorbitol — — — — — — Tyloxapol0.05 0.05 0.05 0.05 0.05 0.05 NaOH/HCl qs qs qs qs qs qs 7.2 ± 0.2 7.3 ±0.2 7.2 ± 0.2 7.3 ± 0.2 6.8 ± 0.2 6.8 ± 0.2 Purified Water qs 100 qs 100qs 100 qs 100 qs 100 qs 100 Observations - Day 1 @ 5° C. PrecipitatePrecipitate Precipitate Clear Precipitate^(d) Precipitate^(d)Observations - Day 6 @ RT Precipitate Precipitate PrecipitatePrecipitate^(c) NA NA Observations - Day 12 @ RT Precipitate PrecipitatePrecipitate Precipitate NA NA Observations - Day 14 @ RT PrecipitatePrecipitate Precipitate Precipitate NA NA ^(a)0.545% Moxifloxacinhydrochloride is equivalent to 0.5% moxifloxacin as base. ^(b)0.132%Dexamethasone sodium phosphate is equivalent to 0.1% dexamethasone.^(c)This sample was stored at 5° C. and observed to have precipitateupon removal from 5° C. The sample was allowed to sit at RT butprecipitate was still observed. ^(d)Precipitate was observed as soon ascompounding was completed.

TABLE 8 Component M^(C) N^(C) O P Q R^(C) S^(C) T U V MoxifloxacinHydrochloride 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a)0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) Dexamethasone0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b)0.132^(b) 0.132^(b) 0.132^(b) Sodium Phosphate Edetate Disodium 0.010.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Boric Acid 0.01 0.01 0.010.01 0.01 0.03 0.03 0.03 0.03 0.03 Sodium Borate 0.44 0.44 0.44 0.440.44 0.42 0.42 0.42 0.42 0.42 Sodium Citrate — — — — — 1.0 1.0 1.0 1.01.0 Sodium Chloride 0.5 0.5 0.5 0.5 0.5 0.27 0.27 0.27 0.27 0.27Sorbitol 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Tyloxapol 0.05 0.050.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 NaOH/HCl qs qs qs qs qs qs qs qsqs qs 6.8 ± 0.2 7.0 ± 0.2 7.1 ± 0.2 7.2 ± 0.2 7.3 ± 0.2 6.8 ± 0.2 7.0 ±0.2 7.1 ± 0.2 7.2 ± 0.2 7.3 ± 0.2 Purified Water qs 100 qs 100 qs 100 qs100 qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 Day 4 Observations NA NAPrecipitate Precipitate Clear NA NA Precipitate Precipitate Clear Day 11Observations NA NA NA NA 1 of 2 NA NA NA NA Clear Precipitate Day 18Observations NA NA NA NA Both NA NA NA NA Clear Precipitate Day 25Observations NA NA NA NA NA NA NA NA NA Clear Day 32 Observations NA NANA NA NA NA NA NA NA Precipitate ^(a)0.545% Moxifloxacin hydrochlorideis equivalent to 0.5% moxifloxacin as base. ^(b)0.132% Dexamethasonesodium phosphate is equivalent to 0.1% dexamethasone. ^(c)Theseformulations were discarded due to precipitate formation at completionof the compounding process.

TABLE 9 Component W X Y Z AA AB AC AD AE AF Moxifloxacin Hydrochloride0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a)0.545^(a) 0.545^(a) 0.545^(a) Dexamethasone Sodium 0.132^(b) 0.132^(b)0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b) 0.132^(b)0.132^(b) Phosphate Edetate Disodium 0.01 0.01 0.01 0.01 0.01 0.01 0.010.01 0.01 0.01 Boric Acid 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 SodiumChloride 0.5 0.5 0.5 0.5 0.5 — — — — — Sorbitol 0.2 0.2 0.2 0.2 0.2 0.20.2 0.2 0.2 0.2 Tyloxapol 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.050.05 NaOH/HCl qs qs qs qs qs qs qs qs qs qs 7.0 ± 0.2 7.3 ± 0.2 7.4 ±0.2 7.8 ± 0.2 7.2 ± 0.2 7.0 ± 0.2 7.2 ± 0.2 7.3 ± 0.2 7.4 ± 0.2 7.8 ±0.2 Purified Water qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 qs100 qs 100 qs 100 Day 10 Observations Precipitate Clear Clear ClearPrecipitate Precipitate Precipitate Precipitate Precipitate Clear Day 17Observations NA Precipitate Clear Clear NA NA NA NA NA Clear Day 24Observations NA NA Clear Clear NA NA NA NA NA Precipitate Day 31Observations NA NA Clear Clear NA NA NA NA NA NA Day 38 Observations NANA Clear Clear NA NA NA NA NA NA Day 45 Observations NA NA Clear ClearNA NA NA NA NA NA 18-week Observations NA NA Clear Clear NA NA NA NA NANA 24-week Observations NA NA Some Clear NA NA NA NA NA NA Precipitate28-week Observations NA NA More Clear NA NA NA NA NA NA Precipitate^(a)0.545% Moxifloxacin hydrochloride is equivalent to 0.5% moxifloxacinas base. ^(b)0.132% Dexamethasone sodium phosphate is equivalent to 0.1%dexamethasone.

Example 10

The composition of Example 2 was subjected to preservative efficacytesting. Antimicrobial preservative effectiveness was determined usingan organism challenge test according to the methods described in theUnited States Pharmacopeia (USP) and European Pharmacopoeia (Ph.Eur.).Samples were inoculated with known levels of one or more of thefollowing: gram-positive (Staphylococcus aureus ATCC 6538) andgram-negative (Pseudomonas aeruginosa ATCC 9027 and Escherichia coliATCC 8739) vegetative bacteria, yeast (Candida albicans ATCC 10231) andmold (Aspergillus niger ATCC 16404). The samples were then pulled atspecified intervals to determine if the antimicrobial preservativesystem was capable of killing or inhibiting the propagation of organismspurposely introduced into the formulation. The rate or level ofantimicrobial activity determines compliance with the USP and/or Ph.Eur.preservative efficacy standards for ophthalmic preparations.

The compendial preservative standards for ophthalmic preparations arepresented below:

For Bacteria:

Log Reduction of Organism Population Ph. Eur. B Time Pull USP Ph. Eur. A(Min)  6 hours — 2 — 24 hours — 3 1  7 days — — 3 14 days 3 — — 28 daysNI NR NIFor Fungi:

Ph. Eur. B Time Pull USP Ph. Eur. A (Min)  7 days — 2 — 14 days NI — 128 days NI NI NI NR = No organisms recovered NI = No increase at this orany following time pulls — = No requirement at this time pull

The results of the microorganism challenge test are shown in Table 10below.

TABLE 10 Composition USP Ph. Eur. B Ph. Eur. A Example 2 Pass Pass Fail

Example 11

The composition of Example 4 was subjected to the same preservativeefficacy testing described in Example 10. Additionally, similarcompositions containing varying concentrations of benzalkonium chloridewere tested. The compositions and the preservative efficacy testingresults are shown in Table 11.

TABLE 11 Components AG AH AI AJ Example 4 Moxifloxacin Hydrochloride,NOC 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) 0.545^(a) DexamethasoneSodium Phosphate, 0.11^(b) 0.11^(b) 0.11^(b) 0.11^(b) 0.11^(b) USPBenzalkonium Chloride, NF 0.0 0.0025 0.005 0.0075 0.01 Edetate Disodium,USP 0.01 0.01 0.01 0.01 0.01 Boric Acid, NF 0.3 0.3 0.3 0.3 0.3 SodiumChloride, USP 0.62 0.62 0.62 0.62 0.62 Tyloxapol, USP 0.05 0.05 0.050.05 0.05 Sodium Hydroxide, NF Adjust pH Adjust pH Adjust pH Adjust pHAdjust pH and/or to to to to to Hydrochloric Acid, NF 7.9 ± 0.1 7.9 ±0.1 7.9 ± 0.1 7.9 ± 0.1 7.9 ± 0.1 Purified Water, USP qs 100 qs 100 qs100 qs 100 qs 100 Preservative Effectiveness Test (PET) Pass USP/EPBPass USP/EPB Pass USP/EPB Pass USP/ Pass USP/ Results Fail EPA Fail EPAFail EPA EPB/ EPB/ EPA EPA ^(a)0.545% Moxifloxacin hydrochloride isequivalent to 0.5% moxifloxacin as base. ^(b)0.11% Dexamethasone sodiumphosphate is equivalent to 0.1%, dexamethasone phosphate.

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

1. A method of treating an otic infection comprising topicallyadministering to the ear a solution composition consisting essentiallyof a) 0.545% (w/v) moxifloxacin hydrochloride; b) 0.11% (w/v)dexamethasone sodium phosphate; c) 0.01% (w/v) edetate disodium; d)0.5-0.75% (w/v) sodium chloride; e) 0.3% (w/v) boric acid; f) 0.01%(w/v) benzalkonium chloride; g) 0.05% (w/v) tyloxapol; h) NaOH or HCl inan amount sufficient to cause the composition to have a pH from 7.8-8.0;and i) water.